rs11591147

This is a variant in the PCSK9 gene that changes a arginine to an leucine.

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GWAS Catalog Trait Associations (228)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

apolipoprotein B measurement

Sinnott-Armstrong N et al. “Genetics of 35 blood and urine biomarkers in the UK Biobank.” Nature Genetics 53(2):185-194 (2021)
Allele T
OR 0.45
p —
N 354,097
Major Consortium StudyLarge GWAS
multi-ancestry
Richardson TG et al. “Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis.” Plos Medicine 17(3):e1003062 (2020)
Allele T
OR 0.35
p —
N 439,214
Large GWAS
European
Karjalainen MK et al. “Genome-wide characterization of circulating metabolic biomarkers.” Nature 628(8006):130-138 (2024)
Allele T
OR 0.37
p 5.0e-142
N 136,016
Large GWAS
multi-ancestry
Richardson TG et al. “Characterising metabolomic signatures of lipid-modifying therapies through drug target mendelian randomisation.” Plos Biology 20(2):e3001547 (2022)
Allele T
OR 0.32
p 2.0e-94
N 115,082
Large GWAS
European
Davyson E et al. “Metabolomic Investigation of Major Depressive Disorder Identifies a Potentially Causal Association With Polyunsaturated Fatty Acids.” Biological Psychiatry 94(8):630-639 (2023)
Allele T
OR 0.32
p 4.0e-71
N 88,329
Large GWAS
European

low density lipoprotein cholesterol measurement

Graham SE et al. “The power of genetic diversity in genome-wide association studies of lipids.” Nature 600(7890):675-679 (2021)
Allele T
OR 0.43
p —
N 1,320,016
Large GWAS
European
Jee YH et al. “Genome-wide association studies in a large Korean cohort identify quantitative trait loci for 36 traits and illuminate their genetic architectures.” Nature Communications 16(1):4935 (2025)
Allele T
OR 0.42
p —
N 928,679
Large GWAS
multi-ancestry
Richardson TG et al. “Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis.” Plos Medicine 17(3):e1003062 (2020)
Allele T
OR 0.35
p —
N 440,546
Large GWAS
European
Sakaue S et al. “A cross-population atlas of genetic associations for 220 human phenotypes.” Nature Genetics 53(10):1415-1424 (2021)
Allele T
OR 0.35
p —
N 416,487
Large GWAS
multi-ancestry
Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)
Allele T
OR 0.42
p 4.0e-294
N 404,687
Major Consortium StudyLarge GWAS
European
Koskeridis F et al. “Pleiotropic genetic architecture and novel loci for C-reactive protein levels.” Nature Communications 13(1):6939 (2022)
Allele T
OR 0.07
p 4.0e-44
N 361,194
Large GWAS
European
Sinnott-Armstrong N et al. “Genetics of 35 blood and urine biomarkers in the UK Biobank.” Nature Genetics 53(2):185-194 (2021)
Allele T
OR 0.48
p —
N 355,197
Major Consortium StudyLarge GWAS
multi-ancestry
Klarin D et al. “Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program.” Nature Genetics 50(11):1514-1523 (2018)
Allele T
OR 0.40
p 3.0e-257
N 297,626
Major Consortium StudyLarge GWAS
multi-ancestry
Karjalainen MK et al. “Genome-wide characterization of circulating metabolic biomarkers.” Nature 628(8006):130-138 (2024)
Allele T
OR 0.42
p 5.0e-179
N 136,016
Large GWAS
multi-ancestry
de Vries PS et al. “Multiancestry Genome-Wide Association Study of Lipid Levels Incorporating Gene-Alcohol Interactions.” American Journal of Epidemiology 188(6):1033-1054 (2019)
Allele T
OR 16.48
p 7.0e-52
N 127,326
Large GWAS
multi-ancestry
Bentley AR et al. “Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids.” Nature Genetics 51(4):636-648 (2019)
Allele T
OR 14.39
p 1.0e-51
N 125,692
Large GWAS
multi-ancestry
Richardson TG et al. “Characterising metabolomic signatures of lipid-modifying therapies through drug target mendelian randomisation.” Plos Biology 20(2):e3001547 (2022)
Allele T
OR 0.33
p 7.0e-99
N 115,082
Large GWAS
European
Hoffmann TJ et al. “A large electronic-health-record-based genome-wide study of serum lipids.” Nature Genetics 50(3):401-413 (2018)
Allele T
OR 0.47
p 6.0e-70
N 94,674
Large GWAS
multi-ancestry
Davyson E et al. “Metabolomic Investigation of Major Depressive Disorder Identifies a Potentially Causal Association With Polyunsaturated Fatty Acids.” Biological Psychiatry 94(8):630-639 (2023)
Allele T
OR 0.29
p 2.0e-59
N 88,329
Large GWAS
European
Surakka I et al. “The impact of low-frequency and rare variants on lipid levels.” Nature Genetics 47(6):589-97 (2015)
Allele T
OR 0.53
p 2.0e-92
N 62,166
Large GWAS
European
Kathiresan S et al. “Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.” Nature Genetics 40(2):189-197 (2008)
Allele T
OR 0.47
p 2.0e-44
N 2,758
Large GWAS
European

free cholesterol in IDL measurement

Karjalainen MK et al. “Genome-wide characterization of circulating metabolic biomarkers.” Nature 628(8006):130-138 (2024)
Allele T
OR 0.46
p 5.0e-222
N 136,016
Large GWAS
multi-ancestry
Davyson E et al. “Metabolomic Investigation of Major Depressive Disorder Identifies a Potentially Causal Association With Polyunsaturated Fatty Acids.” Biological Psychiatry 94(8):630-639 (2023)
Allele T
OR 0.33
p 6.0e-80
N 88,329
Large GWAS
European

total cholesterol in IDL

Karjalainen MK et al. “Genome-wide characterization of circulating metabolic biomarkers.” Nature 628(8006):130-138 (2024)
Allele T
OR 0.46
p 2.0e-220
N 136,016
Large GWAS
multi-ancestry

free cholesterol in large LDL measurement

Karjalainen MK et al. “Genome-wide characterization of circulating metabolic biomarkers.” Nature 628(8006):130-138 (2024)
Allele T
OR 0.46
p 5.0e-220
N 136,016
Large GWAS
multi-ancestry
Davyson E et al. “Metabolomic Investigation of Major Depressive Disorder Identifies a Potentially Causal Association With Polyunsaturated Fatty Acids.” Biological Psychiatry 94(8):630-639 (2023)
Allele T
OR 0.33
p 1.0e-77
N 88,329
Large GWAS
European

phospholipids in IDL measurement

Karjalainen MK et al. “Genome-wide characterization of circulating metabolic biomarkers.” Nature 628(8006):130-138 (2024)
Allele T
OR 0.46
p 1.0e-218
N 136,016
Large GWAS
multi-ancestry
Davyson E et al. “Metabolomic Investigation of Major Depressive Disorder Identifies a Potentially Causal Association With Polyunsaturated Fatty Acids.” Biological Psychiatry 94(8):630-639 (2023)
Allele T
OR 0.33
p 2.0e-81
N 88,329
Large GWAS
European

total cholesterol in large LDL

Karjalainen MK et al. “Genome-wide characterization of circulating metabolic biomarkers.” Nature 628(8006):130-138 (2024)
Allele T
OR 0.46
p 5.0e-217
N 136,016
Large GWAS
multi-ancestry

total lipids in IDL

Karjalainen MK et al. “Genome-wide characterization of circulating metabolic biomarkers.” Nature 628(8006):130-138 (2024)
Allele T
OR 0.45
p 3.0e-214
N 136,016
Large GWAS
multi-ancestry
Davyson E et al. “Metabolomic Investigation of Major Depressive Disorder Identifies a Potentially Causal Association With Polyunsaturated Fatty Acids.” Biological Psychiatry 94(8):630-639 (2023)
Allele T
OR 0.33
p 3.0e-78
N 88,329
Large GWAS
European

esterified cholesterol measurement, intermediate density lipoprotein measurement

Karjalainen MK et al. “Genome-wide characterization of circulating metabolic biomarkers.” Nature 628(8006):130-138 (2024)
Allele T
OR 0.45
p 6.0e-214
N 136,016
Large GWAS
multi-ancestry

cholesteryl esters in large LDL measurement

Karjalainen MK et al. “Genome-wide characterization of circulating metabolic biomarkers.” Nature 628(8006):130-138 (2024)
Allele T
OR 0.45
p 2.0e-213
N 136,016
Large GWAS
multi-ancestry
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ClinVar annotation

Pathogenic★★★☆
19 submitters28 publications

Cardiovascular phenotype; Familial hypercholesterolemia; Hypercholesterolemia, autosomal dominant, 3 (FHCL3); Hypercholesterolemia, familial, 1; Hypobetalipoproteinemia; Hypocholesterolemia; Low density lipoprotein cholesterol level quantitative trait locus 1 (LDLCQ1); not specified

View on ClinVar →
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Research that mentions this SNP (2)

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The dual and opposite role of the TM6SF2‐rs58542926 variant in protecting against cardiovascular disease and conferring risk for nonalcoholic fatty liver: A meta‐analysis
AssociationN=13,577Carlos J. Pirola et al.(2015)· Hepatology

This doctoral thesis comprises three studies on metabolic syndrome-related traits. Study III is a GWAS identifying seven novel loci associating with circulating inflammatory markers (cytokines and adhesion molecules) in 5,284 Finnish individuals from NFBC1966, with meta-analysis including three additional Finnish populations totaling 13,577 participants. Studies I and II use Mendelian randomization and association analysis to examine metabolic effects of lipid-lowering therapies and NAFLD risk alleles (PNPLA3 rs738409-G, TM6SF2 rs58542926-T, GCKR rs780094-T/rs1260326-T, LYPLAL1 rs12137855-C, and NCAN rs2228603-T).

Traits studied:Cardiovascular diseaseCirculating inflammatory markersCytokines and cell adhesion moleculesIL1-betaIL1-receptor antagonistIL17IL4IL6IL8IP10Lipid metabolismMCP1Metabolic syndromeNon-alcoholic fatty liver disease (NAFLD)Soluble E-selectinSoluble ICAM-1Soluble VCAM-1TNF-alphaType 2 diabetes riskVEGF
PubMedDOIMetascience Observatory
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Investigation of genetic risk factors for chronic adult diseases for association with preterm birth
AssociationN=1,792Nadia Falah et al.(2013)· Human Genetics

Case-control study of 673 preterm birth (PTB) cases vs 1,119 controls across four maternal cohorts testing 35 SNPs in cardiovascular, inflammatory, and metabolic disease genes. Found 13 statistically significant associations with PTB (P<0.05), more than expected by chance (binomial P=0.02). Most significant was HLA-DQA1 rs9272346 G allele protective effect in US White mothers (P=0.02, OR=0.65, 95% CI 0.46-0.94), which nominally replicated in Danish cohort (P=0.02, OR=0.85, 95% CI 0.75-0.97) but lost significance after correction for multiple testing.

Traits studied:Cardiovascular diseaseHeight and weightHemostasis and thrombosisHypertensionInflammatory and immunological diseaseLipids and glucose metabolismMyocardial infarctionObesityPreterm birth
PubMedDOIMetascience Observatory

About PCSK9

This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

View all PCSK9 variants →

Gene information from NCBI Gene. Variant classifications from ClinVar.

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